The interaction of the T cell receptor (TCR) with its specific ligand, peptide-MHC, is only one component of the events required for the activation of antigen-specific T cells. The primary goals of our studies are to characterize cell surface antigens (co-receptors) and their soluble or cell associated ligands (counter-receptors) which play critical roles in cell-cell interaction and in the interaction of T cells with their environment. We have concentrated out efforts in a number of distinct areas: 1) We have shown that the cytokine, interleukin-10 (IL-10), inhibits T cell activation by acting on macro-phages and not other types of accessory cells. We have further elucidated the mechanism of action of IL-10 on the inhibition of macrophage costimulatory activity and shown that IL-10 selectively inhibits the upregulation of expression of the B7 antigen which is the cellular counter-receptor for the T cell antigen CD28. The regulation of B7 expression by IL-10 may determine whether T cells become primed or are rendered non-responsive during the generation of an immune response. 2) One model of immunologic tolerance involves the induction peripheral T cell anergy by the injection of adult mice with Staphylococcal enterotoxins. To further characterize the state of a tolerant T cell in vivo, we have established an in vivo model that generates enterotoxin specific IL-4 production. This IL-4 pathway was highly susceptible to tolerogenic signals in both naive T cells and in T cells primed for IL-4 production. The tolerized IL-4 pathway could only be reactivated by expansion during parasite mediated polyclonal activation. These studies should facilitate our understanding of the pathogenesis of autoimmune disease following infectious disease. 3) A number of studies have suggested that the pituitary hormone, prolactin (PRL), plays an important role in immunoregulation. We have demonstrated that T cells, B cells, and macrophages express PRL-receptors and that expression of this receptor on T cells is upregulated during the course of T cell activation. No role for maternal PRL could be defined in the development of the immune system, as the thymic abnormalities seen in the offspring of mothers treated with the PRL secretion inhibitor, bromcriptine, did not appear to be secondary to the decreased level of PRL in their offspring. However, T cells from dwarf mice which have a genetic defect in the synthesis of PRL as well as other pituitary hormones were shown to have a defect in their ability to upregulate the expression of the IL-2 receptor following T cell activation in vivo and this defect could be overcome by administration of PRL.